Novel β‐amino Amide Organocatalysts for the Synthesis of Pharmaceutically Relevant Oxindoles

Abstract

In this work, a series of novel organocatalysts derived from unique unnatural β-amino acid scaffold were synthesized and further developed to enhance the desired catalytic properties. Their evaluation was carried out in the asymmetric crossedaldol condensation of isatin and enolizable ketone donors. Following a systematic study of the reaction parameters including variations of additive, solvent, temperature, catalyst loading and substrate scope, (1R,2R)-2-amino-N-((R)-1-phenylethyl)cyclohexane carboxamide 9 proved particularly successful, affording the corresponding 3-hydroxy-3-alkyl-2-oxindole in excellent yield (> 99%) and distereoselectivity (> 99% dr) with good enantioselective control (up to 52% ee) in the presence of p-nitrophenol and EtOH in < 24 h. An added benefit of this catalyst was its catalytic activity and selectivity at room temperature eliminating the requirement of reduced reaction temperatures. This scaffold, comprising of β-amino amide, has not yet been applied in organocatalysis, thus, this is the first reported in this growing area. In mechanistic studies, direct infusion ESI-MS proved a valuable tool forproposal of the catalytic cycle, confirming the formation of 2 key reaction intermediates.

The synthesis of pharmacologically important oxindoles via the asymmetric aldol reaction of isatin and the investigation of the organocatalytic activity of new alicyclic β-amino acid derivatives

“…In order to achieve good results in enantioselectivity, the presence of another asymmetric site may also be required. 11,28…”

“…The outcome of aldol reactions depends signicantly on solvents used and the amount of solvents. 2,[9][10][11][12][13] When the amount of catalysts was increased, it was usual to witness abrupt drops in ee% followed by sudden increases. As Wang et al reported in 2018, it is likely that this phenomenon is attributed to the retro-aldol reaction.…”

“…[19][20][21][22][23] Over the past 20 years, there has been a strong incentive to develop effective organocatalysts to enhance the asymmetric aldol reaction of isatin and ketones, which is controlled by secondary amine organocatalysts such as proline derivatives. 8,11,[24][25][26] In 2016, Singh et al discovered that proline derivative (S)-N-((S)-1-phenylethyl)pyrrolidine-2-carboxamide has stronger organocatalytic effects than simple (S)-proline. 27 In 2015, Chen et al found that this model reaction was effectively catalysed by the Li + salt of (S)-phenylalanine.…”

Enantioselective Cross‐Aldol Reaction with Ketones and Non‐Enolizable Ketones Catalyzed by Tetrapeptides

“…Amino acids (especially proline) and their derivatives could successfully catalyze the aldol reaction with acetone and isatin. [2,3] Kinsella, [4] Yang, [5] He, [6] Gou [7] and Li [8] and others [9] catalyzed the reaction with catalysts derived from the cyclohexanediamine skeleton. Cinchonaine, [10] terpene [11] and carbohydrate [12] based catalysts are also effective for the reaction.…”

New Mesoporous Silica-Supported Organocatalysts Based on (2S)-(1,2,4-Triazol-3-yl)-Proline: Efficient, Reusable, and Heterogeneous Catalysts for the Asymmetric Aldol Reaction

“…In this context, several representative organocatalysts present two or more functional groups that act in cooperative or bifunctional strategies [12][13][14][15][16][17][18]. Several research groups have used natural and unnatural amino acids and peptides [19][20][21][22][23][24][25][26][27][28][29][30][31], chiral ureas and thioureas [32][33][34][35][36][37][38][39][40], and chiral amides [41][42][43][44][45] as building blocks or templates in organocatalyst design. In this context, a significant number of (S)-proline derivatives have been developed while searching for an improvement in the catalytic efficiency and stereoselectivity [46][47][48][49][50][51][52][53].…”